Therapeutic Strategies for SARS-CoV-2 acting on ACE-2

Dear Editor,

Considering the mechanisms of intracellular penetration of SARS-CoV-2, the significant related risk factors, changes in ACE-2 concentration during infection, and the complex interaction of the RAS system with COVID-19, [1,2] modulation of RAS at certain stages of infection could be considered an important therapeutic strategy. In particular, observational clinical studies indicate that in most cases respiratory problems occur a few days after contracting SRAS-CoV-2 infection, suggesting that this may not be caused by direct viral damage, but suggesting that other mechanisms may be responsible, such as loss of ACE2 function and dysregulation of the RAS system pathways resulting in non-activation of the Ace-2/Ang [1], [2], [3], [4], [5], [6], [7]/Mas receptor axis [3,4] and hyperactivation of the axis Ace/Ang-2/ AT1r. Probably the binding of the peak coronavirus protein leads to exhaustion of ACE2 receptors, which in turn causes the loss of the protective pulmonary function of the ACE2/MAS axis. [5,6] In addition to the loss of protective function of the ACE2/MAS pathway, the resulting hyperactivation of the ACE/AngII/AT1r pathway leads to excessive tissue Ang II production and stimulation of AT1r with vasoconstriction, inflammatory and fibrotic effects contributing to the epithelial lesion of lung tissue. The presence and formation of pulmonary fibrotic tissue in particular can cause serious damage in the pulmonary architecture with consequent physiological dysfunction. [7] The ACE-2 activation pathway on the contrary leads to synthesis of Ang [1], [2], [3], [4], [5], [6], [7] and Ang [1], [2], [3], [4], [5], [6], [7], [8], [9] with stimulation of AT2r receptors with antifibrotic, antiflammatory and vasodilating effects. [8]

Based on this, we believe that in the early stages of viral infection, a decrease or blockage of ACE-2 could reduce the intracellular viral penetration, in the most severe stages of infection where lung dysfunction begins to occur, an increase of ACE-2 for example with soluble ACE-2 (rhACE2) or with RAS acting agents can protect against lung injury. While current evidence does not recommend discontinuation of treatments with RAS modifying agents, we believe that modifications of RAS and ACE-2 at the right time could be important to combat COVID-19 infection. Epidemiological studies are necessary to generate the necessary evidence. [9,10]